METTL3–m6A–IGF2BP2 Axis‐Mediated Stabilization of MTFR1 Promotes Glycolytic Reprogramming in Colorectal Cancer

Vollständiger Abstract

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ABSTRACT Background Metabolic reprogramming fuels colorectal cancer (CRC), yet upstream regulators that lock cells into a glycolytic state remain incompletely defined. Methods We integrated single‐cell and spatial transcriptomics with GWAS–eQTL–Mendelian randomization to nominate CRC‐associated candidate genes, and profiled their expression, spatial localization, and prognostic value in patient cohorts. The function of MTFR1 was tested by proliferation, migration/invasion, EMT marker analysis, and Seahorse extracellular‐flux assays. Mechanisms were interrogated using MeRIP‐qPCR, mRNA stability, and dual‐luciferase assays. In vivo relevance was evaluated in subcutaneous xenografts. Results MTFR1 emerged as a CRC‐associated gene whose high expression was associated with poorer overall and disease‐free survival. MTFR1 silencing curtailed proliferation, migration and invasion, reversed EMT marker changes, reduced glycolytic rate and ATP output, and increased mitochondrial respiration. In mice, stable MTFR1 knockdown significantly restrained tumor growth. Mechanistically, METTL3 deposited m^6A on MTFR1 transcripts, while IGF2BP2 bound MTFR1 mRNA and enhanced its stability, thereby sustaining MTFR1 expression. Conclusion A METTL3–m^6A–IGF2BP2 axis maintains MTFR1 expression to drive glycolytic reprogramming and CRC progression. MTFR1 represents a prognostic biomarker and a potential therapeutic node linking epitranscriptomic regulation to metabolic adaptation in CRC.